Knowledge of the molecular basis of cancer potentially expands the number of strategies to target cancer cells for therapy. Multiple genetic alterations in cancer frequently result in aberrations in the biochemical properties of signaling molecules, leading to dysregulation of signal transduction mechanisms in tumors and consequently malignant progression. As distinct molecular features of tumors compared to normal cells, these molecular changes conceptually provide unique targets for the design of tumor-selective drugs.
Signal Transducer and Activator of Transcription (STAT) proteins are latent cytoplasmic transcription factors that are activated in response to cytokines and growth factors and consequently regulate cellular processes, including proliferation, differentiation and survival (Darnell, J. E., Jr. (2002); Horvath, C. M. (2000); Darnell, J. E., Jr. (1997); Schindler, C. and Darnell, J. E., Jr. (1995); Bromberg, J. and Darnell, J. E., Jr. (2000); Stark, G. R. et al. (1998); Smithgall, T. E. et al. (2000); Akira, S. (2000); Hirano, T. et al. (2000); Kotenko, S. V. and Pestka, S. (2000)). STAT activation is dependent on tyrosine phosphorylation, which induces dimerization via reciprocal phosphotyrosine (pTyr)-SH2 interactions between two STAT monomers and is required for binding to specific DNA response elements (Shuai, K. et al. (1993); Shuai, K. et al. (1994); Sasse, J. et al. (1997)).
A large number of studies on persistent activation of specific STAT family members, particularly Stat3, have established a strong link to growth and survival of transformed and tumor cells (Bowman, T. et al. (2000a); Catlett-Falcone, R. et al. (1999a); Garcia, R. and Jove, R. (1998); Turkson, J. and Jove, R. (2000); Song, J. I. and Grandis, J. R. (2000); Lin, T. S. et al. (2000)). In a number of human solid and hematological tumors, studies have identified a high frequency of abnormal activation of Stat3. In many tumor cells harboring persistent Stat3 activity, inhibition of Stat3 signaling induces growth arrest and apoptosis. The critical role of Stat3 in the molecular pathogenesis of many diverse tumors provides validation for its targeting in cancer drug discovery (Turkson, J. and Jove, R. (2000); Buettner, R. et al. (2002)).